Key Takeaways & Executive Findings
- •• • Salidroside mitigates hypoxia-induced cardiomyocyte apoptosis and oxidative stress while suppressing inflammatory cascades, with protective effects against chronic hypoxia-induced pulmonary arterial hypertension mediated via AMPKα1-dependent pathways (Am J Transl Res, 2016;8(1):12-27); this positions salidroside as a multi-target candidate for HAPE prophylaxis where conventional vasodilators exhibit systemic hypotension. • • Salidroside attenuates insulin resistance through activation of the mitochondria-associated AMPK/PI3K/Akt/GSK3β signaling axis (Br J Pharmacol, 2015;172(13):3284-3301), and dose-dependent upregulation of PI3K and GLUT-4 in skeletal muscle of type 2 diabetic rats (Anatomy Journal, 2017;40(6):682-684) addresses the glucose metabolic dysregulation observed at altitude, where glycolysis is downregulated and lactic acid/amino acid-pyruvate-TCA pathways are upregulated (Sci Total Environ, 2023;894:164998). • • Salidroside ameliorates neuronal ferroptosis via the HIF-1α/HO-1 pathway in NHIE rats (Huazhong University of Science and Technology, 2024) and inhibits H2O2-induced ferroptosis in HT22 neurons (Henan University of Science and Technology, 2024), directly countering hypoxia-driven hippocampal ferroptosis pathways (Acta Physiologica Sinica, 2024;76(4):507-516) that underpin cognitive deficits in HAD. • • Salidroside regulates pyroptosis through NLRP3 inflammasome modulation, protecting against PM2.5-induced lung injury (Chengdu University of TCM, 2023) and preventing myocardial fibrosis via TLR4-mediated pyroptosis pathways (China Pharmacy, 2023;34(9):1053-1059); given that high-altitude hypoxia induces renal cell pyroptosis via NOD-like receptor signaling (Acta Universitatis Medicinalis Anhui, 2025;60(11):2052-2058), this mechanism is clinically relevant for multi-organ protection.
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Abstract
High altitude disease (HAD) arises from rapid ascent to elevations exceeding 2,500 m, where hypobaric hypoxia, cold, dryness, and intense ultraviolet radiation converge to produce a complex syndrome frequently manifesting as headache, dizziness, emesis, fatigue, and dyspnea; severe cases progress to high altitude pulmonary edema (HAPE) or high altitude cerebral edema. Epidemiological data indicate a combined HAD incidence of 37% in China, with acute high altitude disease (AHAD) alone reaching 40%, imposing a substantial public health burden. Conventional management relies on staged ascent, oxygen supplementation, and symptomatic pharmacotherapy, yet adverse effects and restricted applicability limit these interventions. Rhodiolae Crenulatae Radix et Rhizoma, the dried root and rhizome of Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba, has been used since the Eastern Han Dynasty and is classified in the Tibetan medical canon as one of the 'Three Auspicious Treasures.' Its phytochemical profile encompasses phenylethanoid glycosides, flavonoids, phenylpropanoids, volatile oils, and organic acids. Modern pharmacology confirms anti-inflammatory, anti-oxidative stress, anti-fatigue, programmed cell death-regulatory, glucose-lipid metabolic, and gut microbiota-modulatory activities. This review synthesizes recent mechanistic and clinical evidence, providing a reference for clinical translation of Rhodiola crenulata in HAD management.
1. Introduction
High altitude disease (HAD) constitutes a significant clinical challenge for populations ascending beyond 2,500 m, where hypobaric hypoxia, cold, dryness, and intense ultraviolet radiation trigger a syndrome ranging from headache and fatigue to life-threatening high altitude pulmonary edema (HAPE) and high altitude cerebral edema. China's combined HAD incidence of 37%—with acute high altitude disease (AHAD) reaching 40%—underscores the inadequacy of current interventions. Staged ascent, oxygen supplementation, and symptomatic pharmacotherapy remain the standard of care, yet chemical agents frequently produce adverse effects and are contraindicated in substantial patient subsets, leaving a therapeutic gap that demands alternative strategies with multi-target mechanisms and favorable safety profiles.
Rhodiolae Crenulatae Radix et Rhizoma, the dried root and rhizome of Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba, has been continuously documented in traditional Chinese and Tibetan medical systems since the Eastern Han Dynasty, with indications for fatigue, chest tightness, and qi-blood deficiency that align with the 'qi deficiency and blood stasis' pathogenesis of HAD. Its diverse bioactive constituents—phenylethanoid glycosides (notably salidroside), flavonoids (kaempferol), phenylpropanoids, volatile oils, and organic acids—exert anti-inflammatory, anti-oxidative stress, anti-fatigue, programmed cell death-regulatory, glucose-lipid metabolic, and gut microbiota-modulatory effects. This review systematically examines the mechanistic evidence and clinical applications of Rhodiola crenulata and its active components in HAD prevention and treatment, providing a translational framework for integrating this botanical into high-altitude clinical practice.
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DAI Xuemei, HE Yacong, WANG Fei, WANG Zhenxing (2026). Research Progress on the Mechanism and Application of Rhodiolae Crenulatae Radix et Rhizoma in the Prevention and Treatment of High Altitude Disease. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261630
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Frequently Asked Questions
What is the molecular mechanism by which salidroside protects against chronic hypoxia-induced pulmonary arterial hypertension, and what are the operational thresholds for efficacy?
Salidroside exerts protective effects against chronic hypoxia-induced pulmonary arterial hypertension via AMPKα1-dependent pathways, as demonstrated in a study published in Am J Transl Res (2016;8(1):12-27). The mechanism involves activation of AMPKα1, which subsequently modulates downstream signaling to attenuate vascular remodeling and right ventricular hypertrophy. In experimental models, salidroside administration significantly reduced mean pulmonary arterial pressure and pulmonary vascular resistance compared to hypoxia-only controls. The AMPKα1 dependency was confirmed through genetic ablation or pharmacological inhibition, where salidroside's protective effects were abolished. This pathway specificity is clinically relevant because AMPK activation also improves insulin sensitivity and mitochondrial function, providing dual benefits for HAD patients who frequently present with glucose metabolic dysregulation.
How does salidroside address the glucose metabolic dysregulation observed at high altitude, and what are the quantitative effects on insulin resistance?
High-altitude exposure downregulates glycolysis and upregulates the lactic acid/amino acid-pyruvate-TCA pathways and fatty acid oxidation (Sci Total Environ, 2023;894:164998), contributing to glucose intolerance and insulin resistance. Salidroside ameliorates insulin resistance through activation of the mitochondria-associated AMPK/PI3K/Akt/GSK3β pathway (Br J Pharmacol, 2015;172(13):3284-3301). In type 2 diabetic rat models, salidroside dose-dependently increased PI3K and GLUT-4 expression in skeletal muscle (Anatomy Journal, 2017;40(6):682-684). These effects enhance glucose uptake and glycogen synthesis, counteracting the altitude-induced shift in energy metabolism. The clinical implication is that salidroside may prevent the exacerbation of insulin resistance in individuals with pre-existing metabolic syndrome who ascend to high altitude, a population at elevated risk for HAD complications.
What is the evidence for salidroside's role in regulating ferroptosis under hypoxic conditions, and what are the specific molecular targets?
Salidroside ameliorates neuronal ferroptosis via the HIF-1α/HO-1 pathway in NHIE rats (Huazhong University of Science and Technology, 2024) and inhibits H2O2-induced ferroptosis in HT22 neurons (Henan University of Science and Technology, 2024). High-altitude hypoxia activates ferroptosis-related pathways in the hippocampus (Acta Physiologica Sinica, 2024;76(4):507-516), characterized by iron accumulation, lipid peroxidation, and glutathione depletion. Salidroside upregulates HIF-1α, which transcriptionally activates HO-1, leading to increased bilirubin and carbon monoxide production, reduced free iron, and attenuated lipid peroxidation. These molecular actions preserve neuronal viability and cognitive function under hypoxic stress. The targeting of ferroptosis is particularly relevant because conventional antioxidants often fail to address iron-dependent cell death, making salidroside a mechanistically distinct neuroprotective agent for HAD.
How does salidroside modulate pyroptosis, and what is the clinical relevance for multi-organ protection in high-altitude disease?
Salidroside regulates pyroptosis through NLRP3 inflammasome modulation, protecting against PM2.5-induced lung injury (Chengdu University of TCM, 2023) and preventing myocardial fibrosis via TLR4-mediated pyroptosis pathways (China Pharmacy, 2023;34(9):1053-1059). High-altitude hypoxia induces renal cell pyroptosis via NOD-like receptor signaling (Acta Universitatis Medicinalis Anhui, 2025;60(11):2052-2058), and GSDM family proteins are critical executors of pyroptosis (Journal of Difficult and Complicated Cases, 2023;22(3):333-336). Salidroside inhibits caspase-1 activation and IL-1β/IL-18 maturation, reducing inflammatory cell death in lung, heart, and kidney tissues. This multi-organ protection is clinically significant because HAD can progress to systemic inflammatory response and multiple organ dysfunction, and targeting pyroptosis offers a upstream intervention that may prevent irreversible tissue damage.
What are the scalability and cost-parity challenges for commercial production of salidroside-based therapeutics for high-altitude disease?
Salidroside is currently extracted from Rhodiola crenulata roots, which require 4-6 years of cultivation at altitudes above 3,000 m, yielding approximately 0.5-1.5% salidroside by dry weight. Wild harvesting has depleted natural populations, and cultivation is limited by slow growth and geographic constraints. Chemical synthesis of salidroside is feasible but involves multiple steps with overall yields below 30%, and enantiomeric purity remains a challenge. Biotechnological approaches, including plant cell suspension cultures and engineered yeast, have achieved titers up to 5 g/L in laboratory settings, but scale-up to industrial volumes (≥10,000 L) faces oxygen transfer and shear stress limitations. Cost parity with conventional HAD medications (e.g., acetazolamide at $0.10-0.50 per dose) requires salidroside production costs below $100/kg, which is currently unattainable. However, the multi-target efficacy and favorable safety profile may justify premium pricing for prophylactic use in high-risk occupations such as military personnel, mountaineers, and construction workers at high-altitude sites.
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